The n e w e ng l a n d j o u r na l of m e dic i n e

Medicine a nd So cie t y

Debra Malina, Ph.D., Editor

Race and Genetic Ancestry in Medicine

— A Time for Reckoning with Racism
Luisa N. Borrell, D.D.S., Ph.D.,* Jennifer R. Elhawary, M.S.,* Elena Fuentes‑Afflick, M.D., M.P.H.,
Jonathan Witonsky, M.D., Nirav Bhakta, M.D., Ph.D., Alan H.B. Wu, Ph.D.,
Kirsten Bibbins‑Domingo, Ph.D., M.D., José R. Rodríguez‑Santana, M.D.,
Michael A. Lenoir, M.D., James R. Gavin III, M.D., Ph.D., Rick A. Kittles, Ph.D.,
Noah A. Zaitlen, Ph.D., David S. Wilkes, M.D., Neil R. Powe, M.D., M.P.H., M.B.A.,
Elad Ziv, M.D., and Esteban G. Burchard, M.D., M.P.H.*
In the United States, race, ancestry, genetics, and sidered each enslaved African to be three fifths
medicine are inextricably linked in a complex of a person, allowing increased representation
and fraught history. Medicine is replete with for the southern states in the House of Dele-
examples of racial injustice inflicted by the use gates, without what they saw as overtaxation.
of race and ethnicity as biologic constructs to Thus, three racial categories were defined in the
engender hierarchical discrimination. Race and first U.S. Census in 1790 and became deeply
ethnicity are dynamic, shaped by geographic, ingrained in the social fabric of the United
cultural, and sociopolitical forces; they can in- States: White people and Native Americans each
fluence people’s socioeconomic position and lead counted as one whole tax-paying person, and
to disproportionately high morbidity and mor- slaves or Black people counted as three fifths of
tality for racial and ethnic minorities by sustain- a person.2 Although the Three-Fifths Compro-
ing inequitable access to resources, including mise was repealed in 1868, the U.S. Census
health care.1 continues to classify people based on their racial
Nevertheless, we believe that it is inappropri- identification.3
ate to simply abandon the use of race and eth- The Office of Management and Budget classi-
nicity in biomedical research and clinical prac- fies people by ethnicity as well as racial identifi-
tice, since these variables capture important cation.4 Ethnicity (as in Hispanic/Latino) cap-
epidemiologic information, including social de- tures the common values, cultural norms, and
terminants of health such as racism and dis- behaviors of people who are linked by shared
crimination, socioeconomic position, and envi- culture and language, whereas race refers to
ronmental exposures. Eliminating the use of one’s identification with a group or identity as-
race/ethnicity, or implementing a race/ethnicity- cribed on the basis of physical characteristics
blind approach, could enable inequitable health and skin color.5 Census questions are intended
care systems to persist and exacerbate racial/ to reflect self-defined membership in a social
ethnic inequities in health outcomes. Comple- category, without anthropologic or genetic mean-
menting the use of race/ethnicity with data on ing,6 and census data are used to determine re-
genetic ancestry, genotypes, or biomarkers might source allocation and political representation.
be useful, but risks and benefits should be ana-
lyzed carefully for specific clinical applications. R ace a s a Ma s ter S tat us Varia ble
Race is considered a master status,7 or a primary
R acial C ategoriz ations
in the United S tate s identifying characteristic reflecting a social posi-
tion ascribed to a person that may affect every
The 1787 U.S. Constitutional Convention adopt- aspect of their life. Race influences social inter-
ed the “Three-Fifths Compromise,” which con- actions and access to opportunities and societal

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 Medicine and Society
resources.8 For example, race was the driver of
“redlining,” a legal form of residential segrega-
tion9 that resulted in disinvestment in education
and social services, poor housing, limited com-
munity resources such as parks and grocery
stores, unemployment, and poor access to health
care for Black communities.
Race/ethnicity has been used to evaluate dif-
ferences in clinical measures and outcomes and
is used by researchers in established analytic
approaches. Unfortunately, even after analysts
control for socioeconomic indicators such as
education and income, environmental exposures,
and other established risk factors, they frequent-
ly observe a greater risk of adverse health out-
comes among Black Americans than among
White Americans. This increased risk is often
reported without explanation or is presented as
an intrinsic biologic difference between races.
These “intrinsic differences” actually capture
racialized expressions of biology or the embodi-
ment of inequities related to unmeasured risk
factors or exposures, including exposure to indi-
vidual and structural racism.10
Gene tic Ance s try and Admix t ure
In a society in which inequities in health care
affect many disease outcomes, it may seem rea-
sonable to assume that all racial/ethnic differ-
ences in disease incidence and outcomes derive
from socioeconomic differences. However, race
is also directly associated with genetic ancestry
and therefore indirectly related to genetic vari-
ants that may affect disease and health out-
comes. Genomewide genotyping methods and
advanced computational algorithms now enable
scientists to infer the geographic origins of a
person’s ancestors from minute differences in
the cumulative frequency of thousands of ge-
netic variants (alleles). These methods and algo-
rithms have been applied, without bias, to large
populations worldwide. The largest genetic clus-
ters of people correspond to geographic regions
and specific populations in Africa, Europe, Asia,
Oceania, and the Americas,11 suggesting that
continental-level ancestry captures the greatest
population differences in genetic variation. An-
cestry assessment within continents can provide
information on a finer scale.12
Although race/ethnicity correlates with genetic
ancestry,13 it captures different information. Race
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and ethnicity are self-ascribed or socially as-
cribed identities and are often “assigned” by
police, hospital staff, or others on the basis of
physical characteristics. Genetic ancestry is the
genetic origin of one’s population. Although
race/ethnicity may capture information about
the likely presence of certain genetic variants,
ancestry is a better predictor.14 Genetic admix-
ture, or genetic exchange among people from
different ancestries, is an important characteris-
tic of many populations and may correlate with
individuals’ risk for certain genetic diseases.15
And there may be substantial variation in ances-
try among and within populations16; U.S. Black
populations, for example, have larger propor-
tions of African than of European ancestry,
which vary with the year and location in which
samples are obtained.17 Latino Americans, the
largest and fastest-growing U.S. minority popu-
lation, are an admixed group of European, Native
American, and African ancestries (Fig. 1).18
The race/ethnicity categories used in bio-
medical research and clinical practice are broad
and less precise than ancestry. Consider a Black–
White biracial male firefighter who presents
with a smoke-inhalation injury. How would he
be classified? He could self-identify as Black or
White, but society would probably label him as
Black. From a clinical perspective, he is a com-
bination of Black and White. This ambiguity may
contribute to misdiagnosis and is particularly
troubling when someone’s race/ethnicity is as-
signed by health professionals or police. In ad-
dition, different health systems may use differ-
ent racial/ethnic categories. In contrast, ancestry
is a fixed characteristic of the genome.
Ancestry testing using millions of genetic
markers has significantly advanced our under-
standing of globally and geographically diverse
populations, leading to improved clinical predic-
tions. For example, in Black and Latino people,
the proportion of African ancestry predicts dif-
ferences in creatinine levels and estimated glo-
merular filtration rate (eGFR). When 10% of
Latino people initially deemed to have stage 3
chronic kidney disease had their disease reclas-
sified as stage 2 on the basis of ancestry, their
electrolyte levels were more consistent with their
ancestry-adjusted stage than their race-adjusted
stage.19 In addition, validation of the eGFR equa-
tions within three Asian populations yielded
different adjusted predicted values,20 suggesting
475
 The n e w e ng l a n d j o u r na l of m e dic i n e

Native American European African

A Mexican Americans (N=1430)

100

Genetic Ancestry (%)

75

50

25

0
Persons

B Puerto Ricans (N=2181)

100
Genetic Ancestry (%)

75

50

25

0
Persons

Figure 1. Genetic Admixture in the Mexican American and Puerto Rican Populations.
Data are from the Genes-environments and Admixture in Latino Americans (GALA II) Study.

that GFR varies within racial/ethnic groups. We
do not yet know, however, whether ancestry ad-
justment leads to better estimation of GFR than
do race-adjusted or race/ancestry-independent
methods. The alarming decision by some health
care institutions to remove race from GFR calcu-
lations ignores potential population differences
without considering the clinical performance
characteristics or consequences for Black pa-
tients.14,21 Though it may be tempting to con-
sider ancestry in such equations, the true cause
of observed racial differences in creatinine levels
is unknown.
Racial/ethnic differences in risk for disease
and response to treatments are partially related
to biologic factors, including genetic and epigen-
etic variants. Using ancestry as a variable helps
to capture and explain a portion of the biologic
variation between and within groups. For exam-
ple, in the first large-scale epigenetic study of
asthma in minority children, ancestry explained
75% of the total variance in epigenetic patterns,
suggesting that race/ethnicity, as a proxy for
socioenvironmental exposures, explained the re-
maining 25%.22 Thus, race/ethnicity may be bet-
ter than ancestry as a predictor of nongenetic
factors. We would argue that both variables are
important and are complementary in biomedical
research and clinical practice.
Gene tic Ance s try ver sus
Individ ual Clinic al Predic tor s
The National Institutes of Health has made a
concerted effort to include racial/ethnic minority
populations in biomedical and clinical studies.
However, years of inadequate funding for re-
search in these communities have created sig-
nificant knowledge gaps regarding the general-
izability of biomedical discoveries and clinical
advances to non-White populations. Less than
2% of National Cancer Institute–funded clinical
trials have included non-White participants.23
Still, population-specific genetic variants con-

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 Medicine and Society
tributing to clinical differences between racial/
ethnic groups have been identified using a lim-
ited number of racially/ethnically diverse studies.
For example, genetic variants at the 6q25 locus
identified in Latina women are associated with
protection against breast cancer and originate
from Indigenous American populations.24 APOL1
genotypes, which are more common among
people with West African ancestry,25 are strongly
associated with focal sclerosing glomeruloscle-
rosis, nondiabetic kidney disease, and HIV ne-
phropathy, which can lead to early-onset end-
stage kidney failure.26 However, most people
with the high-risk genotype do not have rapid
progression to kidney failure, which suggests
that additional genetic and nongenetic factors
influence its effect.
Prostate cancer is more than twice as com-
mon among Black men as among White men.27
Genomewide association studies have identified
variants at 8q24 that are associated with pros-
tate-cancer risk in many populations, including
variants that are more common in Black men
and account for much of their excess risk of
prostate cancer.28 In another example, a black-
box warning added to Plavix (clopidogrel) in
2010 stated that “poor metabolizers may not
receive the full benefit of Plavix treatment and
may remain at risk for heart attack, stroke, and
cardiovascular death.”29 Among people with no
response to Plavix, as many as 75% of Asians
and Pacific Islanders lack the CYP2C19 genetic
polymorphism required to metabolize the pro-
drug into its active form.29,30 Although there are
examples of genetic variants underlying racial/
ethnic differences in disease occurrence or out-
comes, more often the causes of such differ-
ences are unknown, either because unrecog-
nized nongenetic factors are key or because
genetic research has failed to incorporate racial/
ethnic diversity.31
Globally diverse populations must be studied
because genetic variation and genome architec-
ture vary among populations. More than 80% of
participants in existing genomewide association
studies are of European background; Black and
Latino people, who account for more than 30%
of the U.S. population, are dramatically under-
represented (about 2% and <0.5%, respectively).31
Less than 4.5% of federally funded pulmonary
research has included minority populations, de-
spite evidence of significant population-specific
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differences in the distribution of genetic risk vari-
ants for common diseases such as asthma.32,33
Such disparities perpetuate the gap in access
to precision medicine for non-White populations.
For example, genetic variants within known
cancer risk genes are well identified in popula-
tions of European ancestry, but often the same
variants are classified as “variants of uncertain
significance” in people of non-European ances-
try.34 As the push toward precision medicine in-
tensifies, this worrisome deficit in genetic re-
search will grow, leaving much of the global
population behind. Unless we act now, the
promise of precision medicine will be available
to, and benefit, only a select few.31,35
Furthermore, genetic studies of non-European
populations are important even if genetic vari-
ants are not responsible for overall differences in
disease incidence or outcomes. Specifically, the
frequency and effect sizes of genetic variants as-
sociated with disease risk may vary across popu-
lations.31 Polygenic risk scores derived from
studies of populations with European ancestry
have less predictive power when applied to non-
European populations.31 For example, the poly-
genic risk score for breast cancer is about one
third as predictive for Black women as for
women of European descent,36 a disparity with
clear implications for the future of precision
medicine.
Informed Use of R ace , E thnicit y,
and Ance s try
Race, ethnicity, and ancestry have a complex and
intertwined relationship that demands nuanced
analyses. We believe that associations between
race/ethnicity and disease outcomes should be
interpreted carefully and that we should not as-
sume that environmental, social, or genetic fac-
tors represent the only contributors to a given
disease until causation has been proven. Con-
versely, we should avoid assuming that genetic
causes have been ruled out, as this could under-
mine the discovery of genetic variants like the
8q24 variants that may partially explain increased
prostate-cancer incidence among Black men.28
We believe that decisions regarding the use
of race/ethnicity as a predictor in algorithms
and mathematical risk models should consider
whether the model’s underlying data are strong-
ly associated with race/ethnicity and whether the
477
 The n e w e ng l a n d j o u r na l
inclusion or exclusion of race/ethnicity results
in better health outcomes and reduced health in-
equities. For example, it has been claimed that
race adjustment may overestimate the GFR in
some Black patients and contribute to delays in
referral for renal transplantation, but the nonad-
justed equation may underestimate Black pa-
tients’ GFR, resulting in underdosage or denial
of certain medications or foreclosed opportuni-
ties for kidney donation. An alternative approach
is to calculate the eGFR using cystatin C, a bio-
marker of renal function, instead of creatinine,
but the related testing costs are significantly
higher.
Similarly, race-specific reference equations for
lung function reflect the lower average measures
of normal lung function observed in non-White
groups.37,38 Consequently, relative to the equations
derived from White populations, those derived
from Black populations will yield a higher per-
centage of predicted values for lung function,
which could lead to underestimating the severity
of lung disease, with clinical implications in-
cluding delayed detection, missed opportunities
for medical management of symptoms, denial of
disability claims, and delayed access to lifesav-
ing treatments such as lung transplantation. On
the flip side, using an equation derived from
White populations in other racial/ethnic groups
may lead to overdiagnosis, excessive follow-up
testing, anxiety for patients, and compromised
eligibility for treatments such as stem-cell trans-
plantation for cancer.39 Moreover, the applica-
tion of White-derived lung- and kidney-function
equations to Black patients ignores long-recog-
nized racial/ethnic differences in normal physi-
ological function or biomarkers and is itself a
form of racial discrimination.
As noted above, adjusting eGFR for ancestry
rather than race could result in reclassification
of patients’ kidney disease. However, before an-
cestry adjustment is widely adopted, it is impor-
tant to demonstrate that it provides results at
least as accurate as those of race adjustment.
Ideally, ancestry-adjusted results should be eval-
uated on the basis of prediction of disease or
clinically significant outcomes. In several diverse
cohorts, for example, mathematical risk models
of lung function that included ancestry plus self-
identified race/ethnicity yielded more strongly
predictive results than models including only
self-identified race/ethnicity.40 Data from longi-
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Copyright © 2021 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
tudinal clinical studies of diverse populations
evaluated for kidney and lung disease are need-
ed to determine whether race-based equations,
ancestry-adjusted equations, or equations that ig-
nore both variables better predict clinically sig-
nificant outcomes such as diagnosis, disease se-
verity, prognosis, risk of surgical complications,
and eligibility for lung transplantation. This de-
bate calls attention to the National Institutes of
Health and its disease-focused and organ-based
institutes—that is, the National Institute of Dia-
betes and Digestive and Kidney Diseases and the
National Heart, Lung, and Blood Institute—to
challenge researchers to determine which pre-
diction equation is the most clinically accurate.
Even where there is known genetic variation re-
lated to specific diseases, the use of race/ethnicity
may be important in measuring and addressing
nongenetic causes of health inequities. Although
the higher incidence of prostate cancer among
Black men, for example, may be partially ex-
plained by genetic variants,28 ancestry may be less
important than race/ethnicity in determining
clinical outcomes: among men with prostate
cancer, race/ethnicity is associated with dispari-
ties in access and treatment.41,42
Although some such disparities may be par-
tially captured by careful attention to socioeco-
nomic factors, others may be more deeply rooted
in racial stratification, which drives access to
care, bias, and racial discrimination or racism.
For example, access to organ transplantation is
systematically lower for Black patients with end-
stage renal disease than for their White counter-
parts,43 possibly owing in part to physician
bias.44 Attention to race/ethnicity is important
not only for documenting disparities; interven-
tions designed to reduce disparities have been
demonstrated to improve outcomes.45
Conclusions
Considering genetic ancestry in addition to self-
identified race/ethnicity has improved our under-
standing of disease and facilitated the develop-
ment of interventions. But for many conditions,
the relative importance of bias, racial discrimi-
nation, culture, socioeconomic status, access to
care, environmental factors, and genetics to racial/
ethnic differences in disease has not been ade-
quately studied. The combination of these influ-
ential correlates of health is captured, albeit
 Medicine and Society
imperfectly, by the variable of race/ethnicity, and
ignoring it would be counterproductive.
Indeed, we contend that the epidemiologic
importance of race/ethnicity will never disappear.
Genetic research has advanced our understand-
ing of human disease and therapies that, if made
available equitably, could advance care and pro-
mote health equity in all groups. But we also
recognize that financial, privacy, and societal
costs associated with advances in genetics and
medicine could exacerbate racial/ethnic health
inequities. Therefore, ignoring race and ethnic-
ity in biomedical research and medicine is not
the answer to the health-inequity epidemic. In-
stead, scientists and clinicians should continue
to use racial/ethnic categories to address and
eliminate health inequities until better predic-
tors are available.
By attending to these issues, we can further
elucidate variations in disease onset, progression,
and severity among and within racial/ethnic
groups. Furthermore, given the emergence of
precision medicine and the persistent salience
of overt racism, abandoning race/ethnicity with-
out substituting better disease predictors not only
is irresponsible but also ignores the reality of
U.S. social stratification and its implications for
population health.
Disclosure forms provided by the authors are available at
NEJM.org.
From the Department of Epidemiology and Biostatistics, Grad‑
uate School of Public Health and Health Policy, City University
of New York, New York (L.N.B.); the Departments of Medicine
(J.R.E., J.W., N.B., N.R.P., E.Z., E.G.B.), Pediatrics (E.F.-A., J.W.),
Laboratory Medicine (A.H.B.W.), and Epidemiology and Biosta‑
tistics (K.B.-D.), Priscilla Chan and Mark Zuckerberg San Fran‑
cisco General Hospital (K.B.-D., N.R.P.), the Division of General
Internal Medicine and the Institute of Human Genetics, Helen
Diller Family Comprehensive Cancer Center (E.Z.), and the De‑
partment of Bioengineering and Therapeutic Sciences (E.G.B.),
University of California, San Francisco, San Francisco, Bay Area
Pediatrics, Oakland (M.A.L.), the Department of Population
Sciences, City of Hope Comprehensive Cancer Center, Duarte
(R.A.K.), and the Department of Neurogenetics, University of
California, Los Angeles, Los Angeles (N.A.Z.) — all in Califor‑
nia; the Centro de Neumología Pediátrica, San Juan, PR (J.R.R.-S.);
Emory University School of Medicine, Atlanta (J.R.G.); and the
School of Medicine, University of Virginia, Charlottesville (D.S.W.).
*Dr. Borrell, Ms. Elhawary, and Dr. Burchard contributed equally
to this article.
This article was published on January 6, 2021, at NEJM.org.
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